CN102824304B - Cefepime hydrochloride composition for injection and its preparation method - Google Patents
Cefepime hydrochloride composition for injection and its preparation method Download PDFInfo
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- CN102824304B CN102824304B CN201110160986.5A CN201110160986A CN102824304B CN 102824304 B CN102824304 B CN 102824304B CN 201110160986 A CN201110160986 A CN 201110160986A CN 102824304 B CN102824304 B CN 102824304B
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- 239000007924 injection Substances 0.000 title claims abstract description 41
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- LRAJHPGSGBRUJN-OMIVUECESA-N cefepime hydrochloride Chemical compound O.Cl.[Cl-].S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 LRAJHPGSGBRUJN-OMIVUECESA-N 0.000 title abstract description 12
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Abstract
The invention discloses a cefepime hydrochloride composition for injection. The composition comprises a raw material and auxiliary materials, wherein the raw material is 1000 parts by weight of cefepime hydrochloride and the auxiliary materials contain 710 parts by weight of L-arginine and 10-20 parts by weight of L-lysine. The pH value of the cefepime hydrochloride composition can maintain between 4.0 and 6.0 for a long time. After 12 months of an accelerated test and 24 months of long-term sample storage for observation, contents of related substances are all less than 1%. The invention also aims to provide a preparation method of the cefepime hydrochloride composition for injection. According to the preparation method, the raw materials of cefepime hydrochloride, L-arginine and L-lysine are directly mixed. The preparation technology is simple, and the quality is stable and reliable.
Description
[technical field]
The invention belongs to medical chemistry technical field, relate in particular to a kind of cefepime dihydrochloride for injection composition and method of making the same.
[background technology]
Cefepime hydrochloride (Cefepim, BMY-28142, CFPM) commodity are called Maxipime, be by Bu Mai-Shi Guibao (Bristol-Myers Squibb) company develop successful the 4th generation cephalosporins.In the listing of 1993 Nian Switzerland, successively in multinational listings such as France, Italy, Japan, Canada, the U.S., dosage form is the dry powder injection of 0.5g and two kinds of specifications of 1.0g afterwards.
China gives Bu Mai-Shi Guibao (Bristol-Myers Squibb) Maxipime injectable powder with medicine administrative protection on August 6th, 1999 approval, and stops Maxipime injectable powder in Chinese medicine administrative protection in JIUYUE in 2000 27 days.
1998, Shanghai Shi Guibao company was introduced Bing China and is sold, for clinical.Main Function is in cell wall, the generation of interference cell wall, various cells are all to bactericidal action, so be mainly used in clinically treating urinary tract infection, abdominal cavity infection, respiratory tract infection, the skin and soft tissue infection that sensitive organism causes, also reduce treatment and septicemia and the bacteremic treatment of companion's fever patient for neutrophilic granulocyte.
Title: hydrochloride for injection cephalo arsenic oxime (English name: Cefepim Hydrochloride forInjection)
The chemical name of hydrochloric acid cephalo arsenic oxime: 1-[[(6R, 7R)-7-[2-(2-amino-4-thiazolyl)-glyoxyl is amino]-2-carboxyl-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-3-yl] methyl]-1-methyl arsenic coughs up alkane chloride, 72-(Z)-(0-methyloxime) hydrochloride monohydrate;
Molecular formula: C
19h
25cLN
6o
5s
2hCLH
2o
Chemical structural formula is:
Hydrochloric acid cephalo arsenic oxime architectural feature is: 7 are connected with thiazolamine-α-methoxy imino acetyl group side chain, and 3 exist quaternary ammonium group, and can form inner salt with carboxyl in molecule.Its feature is: because the quaternary ammonium group of 3-bit strip positive charge exists, form amphion, and molecular structure is bullet-shaped, can pass rapidly albumen bypass, make its adventitia see through filter and improved 5-7 doubly, the enhancing of the penetration power of its cell membrane; When keeping third generation cephalosporin characteristic, strengthen G+ bacterium antimicrbial power, anaerobe etc. is had to broad spectrum antibiotic activity; Methicillin-sensitivity staphylococcus and some are produced to the antibacterial of I type beta-lactamase as the effect enhancing of enterobacter cloacae; Penicillin-binding protein is had to high-affinity, stable to beta-lactamase, and long half time, without nephrotoxicity; Compare with third generation cephalosporin, antimicrobial spectrum is wider, and antibacterial activity is stronger.Due to advantages such as this medical instrument has efficiently, low toxicity, wide spectrums, used in a large number clinically determined curative effect, high safety.
The pH value of this medicine raw material hydrochloric acid cephalo arsenic oxime is about 1.6-2.1, must adjust the pH value of this medicine for human body.According to bibliographical information and imported product (Maxipime injectable powder) prescription, knownly add appropriate L-arginine to regulate pH value, can make the pH value of hydrochloride for injection cephalo arsenic oxime maintain 4.0-6.0.
US5095011 discloses a kind of injection cephalo arsenic oxime injectable powder, i.e. Maxipime (Maxipime) injectable powder, and by 375mg arginine and 4.45ml water for injection and 500mg hydrochloric acid cephalo arsenic oxime mixed preparing, pH value is 3-7.
WO2006/106529 also discloses a kind of injection cephalo arsenic oxime injectable powder, major ingredient and L-arginine and water, consists of, and pH value is 3-7.
" research of hydrochloride for injection cephalo arsenic oxime prescription " that can deliver in < < modern food and medicine magazine > > the 16th the 1st phase of volume in the 2006th with reference to Chen Zhenyang, Zhou Xiang etc., by its research, shown, in 1g cephalo arsenic oxime, adding the amount of L-arginine is 720～730mg, within the scope of this, the pH value of this product can maintain between 4.0～6.0, color and clarity, all meet the requirement of American Pharmacopeia (26 editions).
" stability study of hydrochloride for injection cephalo arsenic oxime " delivered in < < drug identification > > the 14th the 12nd phase of volume in the 2005th referring to Wang Haiyang etc., from this research, can find out, commercially available hydrochloride for injection cephalo arsenic oxime is in accelerated test, only sampling check in 1 month, the content of its related substance is just greater than 1%, change more obvious, and in staying for a long time investigation test, also clearly, its stability is also bad as seen in the variation of its related substances.
Reason based on above, in order to find a kind of prescription new, the better hydrochloride for injection cephalo of stability arsenic oxime.I have done a large amount of adjustment L-arginine additions for hydrochloride for injection cephalo arsenic oxime and have found new adjust pH adjuvant test and screening, found that while adding L-arginine 835mg in 1g cephalo arsenic oxime, pH value can maintain 4.5 left and right for a long time, accelerated test 6 months and the investigation 12 months that keeps sample for a long time, its related substances is less than 1%, its color, clarity, bacterial endotoxins etc. all meet the regulation of pharmacopeia, this discovery had announcement in patent No. ZL 200810001184.8, but accelerated test 12 months, keep sample for a long time and investigate 24 months, its related substances is all greater than 1%.
1B is also basic amino acid, in food, adds a small amount of lysine, can stimulate the secretion of pepsin and gastric acid, improves gastric secretion effect, plays the effect of appetite stimulator, promotion physical growth of children and growth.Lysine can also improve the absorption of calcium and accumulation in vivo thereof, accelerates bone growth.As lack lysine, and can cause gastric juice to divide and ooze deficiency and occur anorexia, nutritional anemia, cause that nervus centralis is obstructed, dysplasia.1B is the necessary aminoacid that forms human body all proteins.It,, to regulating internal metabolism balance, improves the absorption to grain protein in body, improves human diet nutrition, and enhancing development all plays an important role.In recent years class, lysine new purposes on medical industry is constantly found, to cause people's extensive concern.Lysine is human body the first limiting amino acids, is listed in nutrition enhancer.China lists food enrichment in lysine and uses sanitary standard, and has developed multiple lysine food, beverage, medicine etc.Li Jian and, " preparation of lysine hydrochlorate for injection and the study on the stability thereof " delivered on the 5th phase at < < Journal of Chinese Hospital Pharmacy > > the 27th volume in 2007 such as lofty, discovery is by the direct lyophilizing of lysine hydrochloride, its freeze-dried products is good, color and luster is pure white evenly, good moldability, redissolution is fast, solution is clear and bright and pH value is suitable, in prescription, need not add excipient mannitol, constant temperature accelerated test and keep sample for a long time test in, stable in properties.Zuo Yongjun etc. show lysine hydrochlorate for injection quality standard research (lysine hydrochloride quality standard research < < China's practical medical > > the 3rd the 12nd phase of volume of April in the 2008th), lysine hydrochloride is freeze-dried powder, clinical practice high safety, has wide market prospect.
Lysine is more and more extensive on medical industry as stabilizing agent and the cosolvent of other drug, " effect of Aspirin-d1-lysine in clinical analgesia " delivered on the 6th phase at < < medical science new knowledge magazine > > the 19th volume in 2009 as Su Yan, Wu Jie etc.; " development of Ibuproben-Lysiante and injection thereof " (journal > > 1994:25 of < < China Medicine University (2): 80-82) that Luan Libiao, Zhang Jun longevity etc. deliver.
Based on above reason, I attempt adding 1B adjust pH in adjuvant, the pleasantly surprised discovery hydrochloric acid of result cephalo arsenic oxime stability obviously strengthens, the amount that adds L-arginine in 1g cephalo arsenic oxime is that the amount of 710mg, 1B is 10～20mg, within the scope of this, the pH value of this product can maintain between 4.0～6.0, accelerated test 12 months, keeps sample for a long time and investigates 24 months, its related substances is all less than 1%, and its color, clarity, bacterial endotoxin etc. all meet the regulation of pharmacopeia.Thereby, for the research of hydrochloride for injection cephalo arsenic oxime provides new prescription.In view of this, special proposition the present invention.
[summary of the invention]
The object of the present invention is to provide a kind of prescription new, the better hydrochloride for injection cephalo of stability arsenic oxime compositions.
To achieve these goals, a kind of hydrochloride for injection cephalo arsenic oxime compositions provided by the invention, the L-arginine that comprised raw material hydrochloric acid cephalo arsenic oxime (in cephalo arsenic oxime), adjuvant, described hydrochloride for injection cephalo arsenic oxime compositions also comprises adjuvant 1B, and the parts by weight of described material composition are:
1000 parts of hydrochloric acid cephalo arsenic oximes
710 parts of L-arginines
10～20 parts of 1Bs,
Wherein, the amount of hydrochloric acid cephalo arsenic oxime is in cephalo arsenic oxime; Adopt following steps preparation with described hydrochloric acid cephalo arsenic oxime compositions:
1) former, adjuvant is removed after outer package, dedusting is clean, and wiping sterilizing enters sterilizing room standby;
2), 100 grades of clean areas, hydrochloric acid cephalo arsenic oxime, L-arginine and 1B are pulverized respectively to rear mistake 80 mesh sieves;
3) 100 grades of clean areas, take step 2) resulting hydrochloric acid cephalo arsenic oxime, L-arginine and 1B, in prescription ratio, mix, survey content and be sub-packed in glass tube vial after qualified, tamponade, roll lid, lamp inspection, be up to the standards, labeling, pack and get final product; With
Get described hydrochloride for injection cephalo arsenic oxime compositions, add water and be mixed with every 1 milliliter of aqueous solution containing cephalo arsenic oxime 0.1g, according to 2000 editions two appendix VI H methods of Chinese Pharmacopoeia, measuring pH value is 4.43～5.18.
Another object of the present invention is to provide a kind of preparation method of hydrochloride for injection cephalo arsenic oxime compositions, described preparation method is that raw material hydrochloric acid cephalo arsenic oxime, L-arginine and 1B are directly mixed.
In the present invention, described preparation method mixes in prescription ratio after being specially supplementary material being pulverized, sieved, after the assay was approved subpackage and get final product.In the present invention, after first supplementary material being pulverized, sieved, remix, can make supplementary material mix more even.
Described sieves as crossing 80 mesh sieves.The object of sieving is in order to obtain the material compared with uniform particle size.This has great importance smoothly to drug quality and preparation production.
Described pulverizing, sieve, mix and subpackage all carries out in 100 grades of clean areas.
Described supplementary material also comprises removal outer package before pulverizing, sieving, dedusting is clean and wiping sterilizing.
Preparation method provided by the present invention specifically comprises the steps:
1) supplementary material is removed after outer package, dedusting is clean, and wiping sterilizing enters sterilizing room standby;
2), 100 grades of clean areas, hydrochloric acid cephalo arsenic oxime, L-arginine and 1B are pulverized respectively to rear mistake 80 mesh sieves;
3) 100 grades of clean areas, take step 2) resulting hydrochloric acid cephalo arsenic oxime, L-arginine and 1B, in prescription ratio, mix, survey content and be sub-packed in glass tube vial after qualified, tamponade, roll lid, lamp inspection, be up to the standards, labeling, pack and get final product.
The present invention provides a kind of new prescription for hydrochloride for injection cephalo arsenic oxime compositions, this prescription is comprised of hydrochloric acid cephalo arsenic oxime, L-arginine and 1B, form rationally, preparation technology is simple, compare with hydrochloride for injection cephalo arsenic oxime of the prior art, its pH value can maintain between 4.0～6.0 for a long time, accelerated test 12 months, keep sample for a long time and investigate 24 months, its related substances is all less than 1%, its color, clarity, bacterial endotoxin etc. all meet the regulation of pharmacopeia, and stability is fine.
[accompanying drawing explanation]
Fig. 1 is the preparation method of cefepime dihydrochloride for injection compositions of the present invention.
[specific embodiment]
For further setting forth the present invention, reach technological means and the effect that predetermined object is taked, below in conjunction with accompanying drawing and preferred embodiment, to the cefepime dihydrochloride for injection composition and method of making the same proposing according to the present invention, its specific embodiment, structure, feature and effect thereof, illustrate as after.
The amount that adds L-arginine in the present invention in 1g cephalo arsenic oxime is that the amount of 710mg, 1B is 10～20mg, within the scope of this, the pH value of this product can maintain between 4.0～6.0, accelerated test 12 months, keep sample for a long time and investigate 24 months, its related substances is all less than 1%, and its color, clarity, bacterial endotoxin etc. all meet the regulation of pharmacopeia.
Embodiment 1
Prescription:
Hydrochloric acid cephalo arsenic oxime (in cephalo arsenic oxime) 1000g
L-arginine 710g
1B 10g
Preparation technology's (referring to accompanying drawing 1):
(1) former, adjuvant is removed after outer package, dedusting is clean, and wiping sterilizing enters sterilizing room standby;
(2), 100 grades of clean areas, hydrochloric acid cephalo arsenic oxime, L-arginine and 1B are pulverized respectively to rear mistake 80 mesh sieves;
(3) 100 grades of clean areas, take hydrochloric acid cephalo arsenic oxime, L-arginine and 1B, in prescription ratio, mix, survey content and be sub-packed in glass tube vial after qualified, tamponade, roll lid, lamp inspection, be up to the standards, labeling, pack and get final product.
Embodiment 2
Prescription:
Hydrochloric acid cephalo arsenic oxime (in cephalo arsenic oxime) 1000g
L-arginine 710g
1B 15g
Preparation technology:
(4) former, adjuvant is removed after outer package, dedusting is clean, and wiping sterilizing enters sterilizing room standby;
(5), 100 grades of clean areas, hydrochloric acid cephalo arsenic oxime, L-arginine and 1B are pulverized respectively to rear mistake 80 mesh sieves;
(6) 100 grades of clean areas, take hydrochloric acid cephalo arsenic oxime, L-arginine and 1B, in prescription ratio, mix, survey content and be sub-packed in glass tube vial after qualified, tamponade, roll lid, lamp inspection, be up to the standards, labeling, pack and get final product.
Embodiment 3
Prescription:
Hydrochloric acid cephalo arsenic oxime (in cephalo arsenic oxime) 1000g
L-arginine 710g
1B 20g
Preparation technology:
(7) former, adjuvant is removed after outer package, dedusting is clean, and wiping sterilizing enters sterilizing room standby;
(8), 100 grades of clean areas, hydrochloric acid cephalo arsenic oxime, L-arginine and 1B are pulverized respectively to rear mistake 80 mesh sieves;
(9) 100 grades of clean areas, take hydrochloric acid cephalo arsenic oxime, L-arginine and 1B, in prescription ratio, mix, survey content and be sub-packed in glass tube vial after qualified, tamponade, roll lid, lamp inspection, be up to the standards, labeling, pack and get final product.
By following experimental example and comparative example, beneficial effect of the present invention is described.
The investigation of [experimental example 1] pH value, color and clarity
Get each of the prepared hydrochloride for injection cephalo arsenic oxime compositions of embodiment 1,2,3, by labelled amount, add respectively water and be mixed with every milliliter containing the aqueous solution of cephalo arsenic oxime 0.1g, correspondence markings is solution 1, solution 2, solution 3 respectively, investigates respectively its pH value, color and clarity.
PH value is measured: sample thief is measured (2000 editions two appendix VI H of Chinese Pharmacopoeia) pH value in accordance with the law.
Colour measurement: sample thief and yellow standard color solution (2000 editions two appendix IX A first methods of Chinese Pharmacopoeia) are relatively.
Clarity is measured: sample thief, as aobvious muddy, compares with No. 1 turbidity standard (2000 editions two appendix IX B of Chinese Pharmacopoeia).
Experimental result table 1:
Table 1.pH value, color and clarity investigation table
| The name of an article | PH value | Color | Clarity |
| Solution 1 | 4.43 | No. 4, < | Clarification |
| Solution 2 | 4.77 | No. 4 | Clarification |
| Solution 3 | 5.18 | No. 4 | Clarification |
By above experimental data, shown, the amount that adds L-arginine in 1g cephalo arsenic oxime is that the amount of 710mg, 1B is 10～20mg, and the pH value of solution (pH4.43～5.18) is between 4.0～6.0, and color is about yellow No. 4, and solution clarification.
[experimental example 2] study on the stability:
(1) factors influencing
Get the prepared hydrochloride for injection cephalo arsenic oxime compositions of embodiment 1,2,3 and carry out respectively illumination (airtight vial, illumination 4000lx), the test of high temperature (60 ℃), low temperature (4 ℃), place 10 days, in the 0th, sampling and measuring indices in the time of 5,10 days.The results are shown in Table 2, table 3, table 4.
Table 2. embodiment 1 hydrochloric acid cephalo arsenic oxime compositions influence factor result of the test
Table 3. embodiment 2 hydrochloric acid cephalo arsenic oxime compositions influence factor result of the tests
Table 4. embodiment 3 hydrochloric acid cephalo arsenic oxime compositions influence factor result of the tests
(2) accelerated test
The sample of getting embodiment 1,2,3 is placed in the thermostatic container that relative humidity (RH) is 75%, is labeled as respectively A, B, C, and in 40 ℃ of baking ovens, constant temperature is placed 12 months, respectively at the 0th, 1,2,6,7,10, during December, samples, and measures indices.Each batch sample shape of result is white powder, odorless, and sterility test is all qualified, and other indexs are in Table 5.
Table 5. accelerated test is investigated result
(3) the room temperature investigation that keeps sample
Get the sample room temperature of embodiment 1,2,3 and place, be labeled as respectively A, B, C, respectively at sampling in the 0th, 3,6,12,15,20,24 months, measure indices.Each batch sample character of result is white powder, odorless, and sterility test is all qualified, and other indexs are in Table 6.
The table 6. room temperature investigation result that keeps sample
The above results shows, the having good stability of product hydrochloride for injection cephalo arsenic oxime of the present invention, and pH value can maintain 4～6 left and right for a long time, and content, related substance are all within the scope of quality standard.
The stability comparison of [comparative example] product of the present invention and commercially available hydrochloride for injection cephalo arsenic oxime
This test example has carried out accelerated test and has kept sample for a long time investigating test to product of the present invention and commercially available hydrochloride for injection cephalo arsenic oxime, and object is stability to compare.
Accelerated test: the product of the present invention in embodiment 1 and commercially available hydrochloride for injection cephalo arsenic oxime are placed in to the thermostatic container that relative humidity (RH) is 75%, in 40 ℃ of baking ovens, constant temperature is placed 12 months, respectively at the 0th, 1,2,6,7,10, during December, sample, measure indices.Each sample shape of result is white powder, odorless, and sterility test is all qualified, and other indexs are in Table 7.
Test for a long time keeps sample: the product of the present invention in embodiment 1 and commercially available hydrochloride for injection cephalo arsenic oxime are placed in room temperature, sampling in the 0th, 3,6,12,15,20,24 months, measured indices respectively.Each batch sample character of result is white powder, odorless, and sterility test is all qualified, and other indexs are in Table 7.
Table 7. accelerated test and room temperature keep sample and investigate test comparative result
By table, can be found out, the hydrochloride for injection cephalo arsenic oxime of product of the present invention is through accelerated test 12 months and the investigation 24 months that keeps sample for a long time, pH value, content and related substance are all without significant change, and commercially available hydrochloride for injection cephalo arsenic oxime is in accelerated test, only time sampling check in 1 month, the content of its related substance is just greater than 1%, its variation is more obvious, and in the investigation test that keeps sample for a long time, the variation of its related substances also clearly, visible, the stability of the hydrochloride for injection cephalo arsenic oxime of product of the present invention is better than commercially available prod.
In this description, the present invention is described with reference to its specific embodiment, still, still can make various modifications and conversion obviously and not deviate from the spirit and scope of the present invention.Therefore, description of the present invention and accompanying drawing are considered to illustrative and nonrestrictive.
Claims (7)
1. a hydrochloride for injection cephalo arsenic oxime compositions, comprises raw material hydrochloric acid cephalo arsenic oxime, adjuvant L-arginine, it is characterized in that, described hydrochloride for injection cephalo arsenic oxime compositions also comprises adjuvant 1B, and the parts by weight of described material composition are:
1000 parts of hydrochloric acid cephalo arsenic oximes
710 parts of L-arginines
10～20 parts of 1Bs,
Wherein, the amount of hydrochloric acid cephalo arsenic oxime is in cephalo arsenic oxime; Adopt following steps preparation with described hydrochloric acid cephalo arsenic oxime compositions:
1) former, adjuvant is removed after outer package, dedusting is clean, and wiping sterilizing enters sterilizing room standby;
2), 100 grades of clean areas, hydrochloric acid cephalo arsenic oxime, L-arginine and 1B are pulverized respectively to rear mistake 80 mesh sieves;
3) 100 grades of clean areas, take step 2) resulting hydrochloric acid cephalo arsenic oxime, L-arginine and 1B, in prescription ratio, mix, survey content and be sub-packed in glass tube vial after qualified, tamponade, roll lid, lamp inspection, be up to the standards, labeling, pack and get final product; With
Get described hydrochloride for injection cephalo arsenic oxime compositions, add water and be mixed with every 1 milliliter of aqueous solution containing cephalo arsenic oxime 0.1g, according to 2000 editions two appendix VI H methods of Chinese Pharmacopoeia, measuring pH value is 4.43～5.18.
2. the preparation method of hydrochloric acid cephalo arsenic oxime compositions claimed in claim 1, is characterized in that, described preparation method is that raw material hydrochloric acid cephalo arsenic oxime, L-arginine and 1B are directly mixed.
3. the preparation method of hydrochloric acid cephalo arsenic oxime compositions as claimed in claim 2, is characterized in that, described preparation method, for after supplementary material is pulverized, sieved, mixes in prescription ratio, after the assay was approved subpackage and get final product.
4. the preparation method of hydrochloric acid cephalo arsenic oxime compositions as claimed in claim 3, is characterized in that, described sieves as crossing 80 mesh sieves.
5. the preparation method of hydrochloric acid cephalo arsenic oxime compositions as claimed in claim 4, is characterized in that, described pulverizing, sieves, mixes and subpackage all carries out in 100 grades of clean areas.
6. preparation method as claimed in claim 5, is characterized in that, described supplementary material also comprises removal outer package before pulverizing, sieving, dedusting is clean and wiping sterilizing.
7. preparation method as claimed in claim 6, is characterized in that, described preparation method comprises the steps:
1) supplementary material is removed after outer package, dedusting is clean, and wiping sterilizing enters sterilizing room standby;
2), 100 grades of clean areas, hydrochloric acid cephalo arsenic oxime, L-arginine and 1B are pulverized respectively to rear mistake 80 mesh sieves;
3) 100 grades of clean areas, take step 2) resulting hydrochloric acid cephalo arsenic oxime, L-arginine and 1B, in prescription ratio, mix, survey content and be sub-packed in glass tube vial after qualified, tamponade, roll lid, lamp inspection, be up to the standards, labeling, pack and get final product.
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| US5244891A (en) * | 1985-08-05 | 1993-09-14 | Bristol-Myers Squibb Company | Injectable compositions of cefepime dihydrochloride hydrate |
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| CN101229128A (en) * | 2007-08-14 | 2008-07-30 | 山东罗欣药业股份有限公司 | Cefepime hydrochloride powder injection and preparing method thereof |
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